Asthma is characterized by allergic airway inflammation and airway remodeling which underlie the clinical characteristics of airflow limitation, bronchial hyperresponsiveness, and susceptibility to exacerbation. Important questions remain for how asthma develops, the mechanisms of allergen sensitization, and the factors that contribute to the persistence of asthmatic airway changes over a lifetime. Here we propose clinical studies to investigate fundamental questions about the role of chitinases and TGFp in initiating and perpetuating allergic asthma. We will combine comprehensive genetic studies with detailed translational studies to address hypotheses for how polymorphisms in chitinase and TGFp pathway genes influence allergen sensitization, asthma susceptibility and expression of asthma-related phenotypes.
Aim 1 will determine the independent and dependent effects of genetic variants in chitinases (AMCase/CHIT1) on sensitization to fungal aeroallergens and other asthma outcomes. Genetic variants in the CHIT1 and AMCase genes will be tested for association with skin test sensitivity to fungal aeroallergens and other asthma phenotypes in a cohort of 1700 asthma cases provided by the Asthma Clinical Research Network and independent cohorts of Latino and African American subjects.
Aim 2 will examine the autonomous and interactive effects of genetic variants in 26 TGFp pathway genes on asthma and asthma-related phenotypes in several large, well-characterized, ethnically diverse asthma family based and case-control cohorts. Associated SNPs will be replicated in independent populations.
Aim 3 will evaluate the functional significance of the genes and genetic variants examined in Aims 1 and 2. We will analyze the relative gene and protein expression of CHIT1 and AMCase in specific lung compartments and the effects of genetic variants on expression of splice variants and levels of airway chitinase activity. We will determine if any of the 26 TGFp pathway genes analyzed show differential expression in the lung in asthma.
Our aims are founded on preliminary data from human subjects and integrate closely with the scientific themes of projects 1 and 2. Together, our studies will greatly advance understanding of the roles of chitinases and TGFp family members in allergy and asthma and could suggest novel treatment approaches. Lay summary: We will examine the effect of genetic variation in the CHIT1, AMCase and TGFp pathway on asthma and asthma related traits in ethnically diverse populations. We will also examine the effect of genetic variation in these genes on gene and protein expression in the lungs of subjects with asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI077439-05
Application #
8376585
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$413,306
Indirect Cost
$144,427
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Sherenian, M G; Cho, S H; Levin, A et al. (2017) PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort. Clin Exp Allergy 47:1150-1158
Sundaram, Aparna; Chen, Chun; Khalifeh-Soltani, Amin et al. (2017) Targeting integrin ?5?1 ameliorates severe airway hyperresponsiveness in experimental asthma. J Clin Invest 127:365-374
Thakur, Neeta; Barcelo, Nicolas E; Borrell, Luisa N et al. (2017) Perceived Discrimination Associated With Asthma and Related Outcomes in Minority Youth: The GALA II and SAGE II Studies. Chest 151:804-812
Yi, L; Cheng, D; Zhang, K et al. (2017) Intelectin contributes to allergen-induced IL-25, IL-33, and TSLP expression and type 2 response in asthma and atopic dermatitis. Mucosal Immunol 10:1491-1503
Reboldi, Andrea; Arnon, Tal I; Rodda, Lauren B et al. (2016) IgA production requires B cell interaction with subepithelial dendritic cells in Peyer's patches. Science 352:aaf4822
Pinkard, Henry; Corbin, Kaitlin; Krummel, Matthew F (2016) Spatiotemporal Rank Filtering Improves Image Quality Compared to Frame Averaging in 2-Photon Laser Scanning Microscopy. PLoS One 11:e0150430
Sen, Debasish; Jones, Stephen M; Oswald, Erin M et al. (2016) Tracking the Spatial and Functional Gradient of Monocyte-To-Macrophage Differentiation in Inflamed Lung. PLoS One 11:e0165064
Meliopoulos, Victoria A; Van de Velde, Lee-Ann; Van de Velde, Nicholas C et al. (2016) An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens. PLoS Pathog 12:e1005804
McAleer, Jeremy P; Nguyen, Nikki L H; Chen, Kong et al. (2016) Pulmonary Th17 Antifungal Immunity Is Regulated by the Gut Microbiome. J Immunol 197:97-107
Thanabalasuriar, Ajitha; Neupane, Arpan S; Wang, Jing et al. (2016) iNKT Cell Emigration out of the Lung Vasculature Requires Neutrophils and Monocyte-Derived Dendritic Cells in Inflammation. Cell Rep 16:3260-3272

Showing the most recent 10 out of 113 publications